INTRODUCTION

The resistance of gram-positive pathogens to currently available antibiotics has increased at an alarming rate, while the development of new effective agents has not kept pace.1 In response to this critical global concern, the Generating Antibiotic Incentives Now Act, part of the Food and Drug Administration Safety and Innovation Act, was signed into law in July 2012 to expedite the development of antibacterials.1 Under this legislation, oritavancin (Orbactiv, The Medicines Company) was designated as a qualified infectious disease product and given priority review by the Food and Drug Administration (FDA).1 It received FDA approval in 2014.

Oritavancin is a new-generation lipoglycopeptide indicated for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible organisms, including Staphylococcus aureus (methicillin-susceptible [MSSA] and methicillin-resistant [MRSA] strains), certain Streptococcus species, and Enterococcus faecalis.2 It is a bactericidal agent that exhibits concentration-dependent activity.2 Trials to evaluate the use of oritavancin for other complicated infections, such as bacteremia and osteomyelitis, are currently being conducted.3,4 Two additional second-generation lipo-glycopeptides—dalbavancin (Dalvance, Allergan) and telavancin (Vibativ, Theravance Biopharma)—have also been approved by the FDA.1 This article will focus on oritavancin.

CHEMICAL STRUCTURE

Oritavancin, a second-generation, semi-synthetic lipoglycopeptide, is derived from chloroeremomycin, an analogue of vancomycin.5 Similar to vancomycin, it contains a core heptapeptide; however, its unique lipophilic side chain provides oritavancin with a prolonged half-life compared to the parent drug.3,6 Oritavancin also offers enhanced coverage against vancomycin-susceptible enterococci, vancomycin-resistant enterococci (VRE), and vancomycin-intermediate and vancomycin-resistant staphylococci due to its N-alkyl-p-chlorophenylbenzyl substituent on the disaccharide sugar, allowing binding to a secondary site on the peptidoglycan layer called the pentaglycyl bridge.3 The drug’s chemical structure is illustrated in Figure 1.

CLINICAL PHARMACOLOGY

Mechanism of Action

Oritavancin has a multifaceted mechanism of action that exhibits concentration-dependent effects against gram-positive organisms.3,6 Similar to vancomcyin and other glycopeptides, oritavancin inhibits cell wall biosynthesis by binding noncovalently to the D-alanyl-D-alanine terminal ends of the peptidoglycan chain and pentaglycine bridge, thereby inhibiting transglycosylation and transpeptidation.3,6 Specifically, the bond of oritavancin to D-alanyl-D-alanine allows for its activity against VanA-resistant isolates.7 Structurally, its hydrophobic side chain (4′-chlorobiphenylmethyl) not only increases binding affinity, but also allows disruption of bacterial membrane potential, leading to increased permeability in resistance phenotypes.3,6 This side chain allows the formation of a dimer, involving the disaccharides on ring four and six, anchoring the drug to the bacterial cell membrane, improving oritavancin’s ability to bind to its target.3,6 Unique to oritavancin is its ability to inhibit bacterial RNA synthesis, allowing rapid bactericidal eradication.8 The multipronged mechanism of oritavancin allows action against resistance patterns instituted by gram-positive isolates.7

Pharmacokinetics and Pharmacodynamics

Oritavancin displays linear pharmacokinetics when administered at intravenous (IV) doses ranging from 0.02 to 10 mg/kg.11 It is bound to approximately 85% of human proteins.11 Based on population kinetics, the half-life of oritavancin is 393 hours, allowing for a single-dose strategy. The total volume of distribution is approximately 87.6 L, which indicates oritavancin is extensively distributed into the tissues, including the liver, kidney, spleen, and lungs.11,12 The penetration of oritavancin into blister fluid in humans provides stable concentrations that provide an area under the curve (AUC) that is approximately 18% of the AUC in serum.12 Oritavancin does not undergo hepatic metabolism.12 It remains as unchanged drug and is excreted in the feces (less than 1%) and the urine (less than 5%) within two weeks of administration.12In vitro studies have shown the ability of oritavancin to accumulate extensively in macrophages, potentially enhancing the eradication of pathogens that survive in lysosomes.13

Belley et al. utilized an in vitro pharmacokinetics/pharmacodynamics model that revealed the potent antibacterial activity of a single 1,200-mg dose of oritavancin and its rapid effect within the first two to three hours against MRSA.14 Oritavancin displays concentration-dependent killing and is best observed with exposures maximizing the peak concentration/MIC or AUC/MIC ratios.14 The long post-antibiotic effect was sustained over 72 hours, and oritavancin maintained its bactericidal activity in the stationary phase and against biofilms.3 Resistance to oritavancin was not observed in clinical studies.

Oritavancin displays synergistic activity when used in combination with other antimicrobial agents, such as gentamicin, moxifloxacin, and rifampin, against MSSA.15 Specifically, synergistic activity was observed in the killing of vancomycin-intermediate S. aureus (VISA), heterogeneous VISA, and vancomycin-resistant S. aureus (VRSA) when used with gentamicin or linezolid, and against VRSA when used with rifampin.15 Antagonism was not observed between oritavancin and gentamicin, moxifloxacin, linezolid, or rifampin.15In vitro data evaluating synergy of oritavancin with ceftaroline, carbapenems, or ampicillin for VRE suggest some VRE faecium strains may be susceptible; however, VRE faecalis strains did not respond in a similar way.16

CLINICAL STUDIES

Phase 2 Trials

SIMPLIFI was a multicenter, randomized, double-blind, phase 2 trial evaluating the safety and effectiveness of infrequent dosing of oritavancin in 302 adult patients with complicated skin and skin structure infections (cSSSIs). Patients received IV oritavancin 200 mg daily for three to seven days (daily-dose group), a single dose of 1,200 mg (single-dose group), or a single 800-mg dose on day 1 with an optional 400-mg dose on day 5 (infrequent-dose group). The clinical cure rates among 228 clinically evaluable patients were 72.4% in the daily-dose group, 81.5% in the single-dose group, and 77.5% in the infrequent-dose group. Although insufficiently powered to detect any differences, the clinical cure rates among the subset of patients with MRSA infections ranged from 78.3% to 87.0% and were not significantly different. The results of this study demonstrated that single and infrequent doses of oritavancin were noninferior to daily dosing with comparable safety profiles for the treatment of cSSSIs.17

Study SD001, a multicenter, randomized, double-blind, phase 2 trial, was conducted by Arhin and colleagues to determine the susceptibility to oritavancin and vancomycin of pairs of S. aureus isolates from nasal swabs at baseline and test-of-cure visits. The objective was to determine whether oritavancin therapy would lead to reduced susceptibility to the drug in isolates from the nares. Patients received one of three IV oritavancin regimens: a single dose of 1,200 mg, 200 mg daily for three to seven days, or 800 mg on day 1 with an optional dose on day 5. The dose of vancomycin was not discussed. S. aureus was isolated in 124 of 545 nasal swabs. Baseline MICs were 0.008–0.5 mg/L for oritavancin and 0.25–1.0 mg/L for vancomycin. Oritavancin treatment was not associated with changes in oritavancin and vancomycin susceptibility among S. aureus nasal isolates.18

Phase 3 Trials

Two phase 3, double-blind, noninferiority trials (SOLO I and SOLO II) evaluated the efficacy and safety of infrequent dosing of oritavancin versus vancomycin for the treatment of ABSSSI. In accordance with a 2010 FDA guidance for industry, the SOLO trials were designed to assess novel primary endpoints for ABSSSI.19,20 The trial results are summarized in Table 1.

The SOLO I trial randomized 968 adult patients to receive either a single dose of oritavancin 1,200 mg or vancomycin 1 g or 15 mg/kg twice daily for seven to 10 days with therapeutic drug monitoring. The primary composite endpoint consisted of the following: cease in the spread or a reduction in lesion size, absence of fever, and no need for a rescue antibiotic. In the modified intention-to-treat (mITT) population, the composite endpoint occurred in 82.3% and 78.9% in the oritavancin and vancomycin arms, respectively. An improvement in lesion size at 48–72 hours was observed in 86.9% with oritavancin and 82.9% with vancomycin; however, this difference was not statistically significant.19

In the SOLO I trial, 164 patients had confirmed MRSA infections at baseline. Of these patients, 80.8% in the oritavancin group and 80.0% in the vancomycin group achieved the composite endpoint. Clinical cure was 82.7% versus 83.0%, and a reduction in lesion size by 20% or greater was 90.4% versus 84.0% in the oritavancin and vancomycin arms, respectively. In patients with confirmed MSSA infections, 82.8% in the oritavancin arm and 83.6% in the vancomycin arm met the primary composite endpoint. Clinical cure was observed in 76.7% of patients receiving oritavancin and 80% of patients receiving vancomycin. An improvement in lesion size at 48–72 hours was observed in 84.5% with oritavancin and 85.5% with vancomycin.19

The SOLO II trial randomized patients to receive a one-time dose of 1,200 mg oritavancin (n = 503) or seven to 10 days of twice-daily vancomycin (n = 502). The primary composite endpoint was the same as that of the SOLO I trial. In the mITT population, the composite endpoint was achieved in 80.1% and 82.9% in the oritavancin and vancomycin arms, respectively. An improvement in lesion size at 48–72 hours was observed in 85.9% with oritavancin and 85.3% with vancomycin.20

In this study, 100 patients had confirmed MRSA infections at baseline. Of these patients, 82.0% in the oritavancin arm and 81.2% in the vancomycin arm achieved the composite endpoint. Clinical cure was 84.0% versus 85.1%, and a reduction in lesion size of 20% or greater was 96.0% versus 90.1% in the oritavancin and vancomycin arms, respectively. In patients with confirmed MSSA infections, 84.0% in the oritavancin arm and 87.3% in the vancomycin arm met the primary composite endpoint. Clinical cure was observed in 86.7% with oritavancin and 86.6% with vancomycin. An improvement in lesion size at 48–72 hours was observed in 87.3% with oritavancin and 86.0% with vancomycin. Similar to the SOLO I trial, this study demonstrated the noninferiority of oritavancin to vancomycin.20

Subsequent to the SOLO trials, Corey and colleagues conducted a pooled analysis assessing clinical responses by pathogen at 48–72 hours and at study days 14–24. Of the 1,959 patients in the pooled SOLO studies, 1,944 had S. aureus isolated, of which 405 were MRSA. Most patients came from the U.S. and the Panton-Valentine leukocidin gene was found in 40% of MSSA isolates and in more than 90% of MRSA isolates at baseline. This pooled analysis demonstrated the clinical efficacy of oritavancin compared with multidose vancomycin, even in the setting of resistant genes commonly seen in clinical practice.21

ADVERSE DRUG REACTIONS

The most common adverse reactions related to oritavancin in clinical trials were nausea, vomiting, headache, diarrhea, vomiting, phlebitis, extravasation, infusion-related reactions, hypersensitivity, cellulitis, and constipation.17,19–21 Slight elevations in liver enzymes also occurred in patients administered oritavancin; however, no lab values or symptoms related to liver function tests led to discontinuation of the drug.4,19 An increase in blood creatine phosphokinase was also seen, but all instances were mild and asymptomatic.17 Although similar in structure to vancomycin and telavancin, oritavancin did not exhibit nephrotoxicity, ototoxicity, or QTc prolongation.22

The recommended oritavancin dosage for the treatment of ABSSSI is 1,200 mg administered as a single infusion. The drug is supplied as a powder for solution in three vials, each containing 400 mg; all three vials are required for the recommended dose. Each vial should be reconstituted with 40 mL of sterile water for injection to produce a concentration of 10 mg/mL. Oritavancin should be diluted further with dextrose in sterile water because other solutions may cause precipitation. Reconstituted vials and diluted solutions may be stored for 12 hours under refrigeration or for six hours at room temperature.

Oritavancin is infused over three hours and should not be administered simultaneously through the same IV line as other medications mixed with saline-based solutions. If the line is to be used for other medications, properly flush the line prior to and after each infusion with dextrose in sterile water. Consult the full prescribing information for dosage, preparation, and administration details.

Oritavancin should not be administered in the absence of a susceptible isolate due to the concern of development of drug-resistant bacterial species.

Hypersensitivity reactions have been reported in studies and may be delayed due to the drug’s prolonged half-life. Patients with confirmed glycopeptide allergies should be monitored closely. If a hypersensitivity reaction develops, therapy should be discontinued and supportive treatment administered. Oritavancin is not removed by hemodialysis.

Infusion-related reactions (pruritus, phlebitis, urticaria, and flushing) have been reported in less than 4% of patients. Providers should consider slowing or interrupting infusions if reactions occur. Patients should be educated to seek immediate medical attention if a reaction occurs after administration.

Clostridium difficile-associated diarrhea has been reported and has occurred more than two months after treatment with oritavancin. Patients who have persistent watery or bloody stool should contact their health care provider for further evaluation.

In phase 3 ABSSSI trials, a greater incidence of osteomyelitis was reported in oritavancin-treated patients compared with vancomycin-treated patients. Patients should be monitored for signs and symptoms of osteomyelitis, and appropriate antimicrobial therapy should be initiated if diagnosis is confirmed.

Contraindications

Oritavancin is contraindicated in patients who have a known hypersensitivity to the agent. In addition, the use of IV unfractionated heparin is contraindicated for 120 hours (five days) after oritavancin administration due to false elevation of activated partial thromboplastin time in this time period.

Drug–Drug Interactions

Avoid administering the drug concomitantly with medications with a narrow therapeutic window that are predominantly metabolized by one of the affected CYP450 enzymes, as coadministration may increase or decrease concentrations of the narrow therapeutic range drug. Patients should be monitored closely for signs of toxicity or lack of efficacy if they have been given oritavancin while on a potentially affected compound (e.g., patients should be monitored for bleeding if concomitantly receiving oritavancin and warfarin).

Drug–Laboratory Interactions

Oritavancin may artificially prolong certain laboratory coagulation tests by binding to and preventing the action of the phospholipid reagents that activate coagulation in commonly used tests.

Special Populations

Pregnancy and Lactation

There are no available human data on the effects of oritavancin in pregnant or lactating women. In animal reproduction studies, no adverse events were observed in pregnancy; however, oritavancin was excreted in the milk of lactating rats. Oritavancin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, and caution should be exercised when oritavancin is administered to a nursing woman.

Renal and Hepatic Impairment

Dosage adjustments are not needed in patients with mild-to-moderate renal or hepatic impairment. However, caution is advised in patients with severe renal or hepatic impairment, as these populations have not been studied.

Geriatric and Pediatric Use

The safety and efficacy of oritavancin have not been studied in people younger than 18 years of age. There were too few patients 65 years of age and older in the pooled phase 3 trials to determine whether these patients respond differently than those who are younger; however, greater sensitivity of some older individuals cannot be ruled out.

P&T COMMITTEE CONSIDERATIONS

Given the emergence of MRSA as a common pathogen causing skin infections, empirical therapy has shifted from beta-lactam antibiotics to agents with anti-MRSA coverage. Oritavancin offers clinicians another treatment modality in the setting of rising resistance in gram-positive bacteria. Oritavancin has the advantage of achieving stable MICs and allowing for convenient one-time dosing.

When selecting an antibiotic, it is important to consider drug cost, the necessity for an infectious disease consultation to ensure appropriateness, and the follow-up requirements to confirm eradication of the infection. Approval by an infectious disease pharmacist, fellow, or physician should be considered to prevent use of oritavancin in unwarranted situations. The benefits of cost reduction and compliance make oritavancin desirable for formulary consideration; however, a multidisciplinary approach should be utilized to ensure appropriate use.

The average wholesale price of oritavancin is $3,480 for a package of three 400-mg vials, all of which are used for the 1,200-mg recommended dose.23

FUTURE TRENDS

Limiting resistance is a multipronged effort that includes correct prescribing and appropriate use and limitations, as well as ensuring therapy completion on the patient side. In response to pressures to decrease health care spending, management of ABSSSI is transitioning to the outpatient sector.24 Future development of therapies for the management of ABSSSI seem to be geared toward convenience in providing timely care in the outpatient setting, allowing for more efficient and less costly treatment.24

CONCLUSION

Oritavancin provides a convenient one-dose treatment option for ABSSSI due to resistant gram-positive organisms. In phase 3 trials, one 1,200-mg dose of oritavancin demonstrated noninferiority to a seven- to 10-day course of vancomycin.19,20 With its multimodal mechanism of action and prolonged half-life, oritavancin is a next-generation option in the setting of growing antibiotic resistance.

Dr. Rosenthal is a Clinical Pharmacy Specialist in Emergency Medicine at Bryn Mawr Hospital in Bryn Mawr, Pennsylvania. Dr. Decano is a Clinical Pharmacotherapy Specialist in Infectious Diseases at New York University Lutheran Medical Center in Brooklyn, New York. Dr. Bandali is a PGY1 Pharmacy Resident at Hahnemann University Hospital in Philadelphia, Pennsylvania. Dr. Lai is a Clinical Trials Research Pharmacist at Dana-Farber Cancer Institute’s Yawkey Center for Cancer Care in Boston, Massachusetts. Dr. Malat is a Clinical Pharmacist in Solid Organ Transplant at Drexel University College of Medicine in Philadelphia, Pennsylvania. Dr. Bias is a Clinical Pharmacy Specialist in Infectious Diseases at Hahnemann University Hospital. Drug Forecast is a regular column coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi and Associates in New York, New York.

About P&T®

Editor-in-Chief

David Nash, M.D, M.B.A., Editor in Chief

David B. Nash, MD, MBA, editor-in-chief of P&T, is Dean of the Jefferson College of Population Health, Philadelphia. From 1996 to 2003, he served as the first Associate Dean for Health Policy at Jefferson Medical College. In 2004, he was named Co-director of the Master’s Program in Public Health at Jefferson.